Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States, with mortality almost exclusively attributed to metastatic liver disease. Therefore, understanding the mechanisms governing how a primary tumor grows and disseminates to secondary sites is of great clinical importance. There is increasing evidence suggesting that genetic background is an important determinant of metastatic susceptibility, but little is known about the specific genetic factors that affect CRC. The proposed research will develop a mouse model of CRC that will allow the investigation of whether genetic background influences tumor development, progression, and metastases through interaction with specific transforming mutations. Tumor growth, histopathological analysis, and gene expression analysis will be used to characterize cancer development in the new model and compare it to an existing CRC mouse model that utilizes a different tumor initiating event. Similar analyses will be performed on mice with differing maternal genotypes and cooperating mutations to investigate how the mutations and genetic background interact to influence tumor progression. The long-term goal of this research is to be able to predict which patients have a higher risk of metastatic disease and develop more appropriate therapeutic strategies for these individuals. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related deaths in developed countries, with mortality almost exclusively attributed to dissemination of cancer cells to other parts of the body (i.e. metastasis). Understanding the genetic factors that influence colorectal cancer metastasis will aid in identifying patients predicted to have a higher risk of metastatic disease and could have a significant impact on intervention strategies for these patients.